Neuroimaging signatures of autism: Linking brain function to genes and behavior

自闭症的特点是巨大的表型异质性可能是由于其复杂的遗传和神经基础。来自我们自己实验室和其他实验室的研究提供了越来越多的证据表明，自闭症谱系障碍（ASD）患者对社会刺激的反应性降低，大脑连接模式改变。此外，我们最近发现，异常的功能和结构连接与遗传易感性显着相关的疾病。尽管取得了这些重大进展， 关于（i）可能导致我们先前表征的对社会刺激的减少的镜像和奖励相关反应的潜在机制，（ii）这些回路的功能与异常连接之间的关系，（iii）后者在多大程度上反映了ASD中改变的发育轨迹的原因或影响，更广泛地说，（iv）ASD的已知遗传风险因素如何影响支持复杂社会行为的大脑回路。拟议 研究旨在解决这些问题，同时寻求在ASD的竞争神经生物学账户之间建立协同作用。利用我们的NIH资助的ASD儿童研究的历史，从而有机会研究以前表征的队列，我们处于独特的地位，可以系统地绘制ASD儿童和非ASD儿童大脑活动和连接的纵向变化，并将观察到的发育轨迹与行为表型和自闭症风险基因联系起来。 更具体地说，使用交叉滞后纵向设计，我们将在两个时间点（间隔3年）在两个先前表征的年龄组（首次评估时为6-9岁和12-14岁）中进行功能性磁共振成像（fMRI），静息状态fMRI（rs-fMRI）和弥散张量成像（DTI），并将这些数据与行为表型和ASD风险多态性相关联。这种综合研究方法将 利用每种研究方法的优势，以及它们之间的协同作用，以确定最早的偏离典型的发展和描绘基因，大脑和行为之间的复杂相互作用，驱动和限制社会大脑ASD的非典型发展。

Autism is characterized by tremendous phenotypic heterogeneity likely due to its complex genetic and neural underpinnings. Research from our own lab and others' have provided mounting evidence of decreased responsivity to social stimuli and altered patterns of brain connectivity in individuals with autism specrum disorders (ASD). Moreover, we have recently shown that aberrant functional and structural connectivity is significantly related to genetic vulnerability to the disorder. Despite these significant strides, critical questions remain unanswered with regard to (i) the underlying mechanisms that may give rise to the reduced mirroring and reward-related responses to social stimuli we have previously characterized, (ii) the relationship between the functioning of these circuits and aberrant connectivity, (iii) the extent to which the latter reflects the cause or the effect of altered developmental trajectories in ASD and, more broadly, (iv) how known genetic risk factors for ASD impact brain circuitry subserving complex social behaviors. The proposed studies are designed to address these issues, while seeking to build synergy amongst competing neurobiological accounts of ASD. Capitalizing on our history of NIH funded research in children with ASD, and thus the opportunity to study previously characterized cohorts, we are uniquely positioned to systematically chart longitudinal changes in brain activity and connectivity in children with and without ASD, and to relate the observed developmental trajectories to both behavioral phenotypes and autism risk genes. More specifically, using a cross-lagged longitudinal design, we will perform functional magnetic resonance imaging (fMRI), resting-state fMRI (rs-fMRI) and diffusion tensor imaging (DTI) at two timepoints (3 years apart) in two previously characterized age cohorts (6-9 & 12-14 years of age at first assessment) and relate these data to behavioral phenotypes and ASD risk polymorphisms. This integrated research approach will exploit the strengths of each investigative method, as well as the synergy amongst them, to identify the earliest departures from typical development and delineate the complex interactions among genes, brain,and behavior that drive and constrain the atypical development of the social brain ASD.